1. Field of the Invention
The present invention relates to water-soluble curcumin complexes. In particular, the invention concerns aqueous compositions containing water-soluble and stable curcumin complexes. The invention also concerns methods of solubilizing curcumin by forming stable cyclodextrin complexes. Further, the present invention relates to medical, pharmaceutical and nutraceutical formulations of curcumin and a composition and methods of protecting cells and organs.
2. Description of Related Art
Curcumin, chemically called diferuloylmethane, is a hydrophobic polyphenol derived from the rhizome of the perennial herb Curcuma longa. It has a wide spectrum of biological and pharmacological activities. Curcumin isolated from turmeric powder contains two other curcuminoids, demethoxycurcumin and bisdemethoxycurcumin, which differ in their biological activities. Curcumin is the most active curcuminoid in most in vitro bioassays but even the other curcuminoids have proven effective in some disease models.
Curcumin has been shown to exhibit potent anti-inflammatory, immunomodulatory, antiproliferative and anticarcinogenic activities and protect cells and tissues against various injury mechanisms. A number of preclinical studies have indicated that curcumin is a promising therapeutic agent for several diseases and clinical conditions, including, for example, the treatment of cancer and leukemias, stroke, myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, pancreatitis, sepsis, hemorrhagic shock, organ transplantations, and radiation injury.
Several molecular targets have been identified for curcumin, and the interactions of curcumin with these targets explain at least part of the therapeutic effects identified in animal disease models. Furthermore, curcumin has proved to be remarkably safe in animal studies and phase I clinical trials even at high dose levels.
The major problem limiting the exploitation of curcumin's potentially valuable therapeutic effects is its low bioavailability. In practice, only very low or undetectable levels of curcumin can be achieved in blood by oral administration of curcumin (1). The low bioavailability of curcumin has so far limited its medical use.
The main reasons contributing to the low bioavailability of curcumin are its very low aqueous solubility and rapid intestinal metabolism, particularly in human subjects. Furthermore, the low aqueous solubility and poor stability of curcumin have hindered the development of pharmaceutical formulations suitable for parenteral and mucosal administration, which would lead to effective concentrations of curcumin in tissues.
Various methods have been tried to enhance curcumin delivery, including its incorporation into liposomes and nanoparticles. So far these formulations have not been shown to deliver effective concentrations of curcumin into tissues or to enable the treatment of diseases and injuries affecting organs like the brain, lungs, kidney, liver or bladder.
A few publications have addressed interactions of curcumin with cyclodextrins (2,3,4). Cyclodextrins are cyclic oligosaccharides consisting of α(1-4)-linked glucopyranose units, which form a lipophilic cavity and a hydrophilic outer surface. Their apolar cavity is able to include hydrophobic molecules by non-covalent forces and thereby improve their water solubility. However, the reported experiments suggest that only low concentrations of curcumin can be solubilized even with a high molar excess of cyclodextrins. The hydrolytic stability of curcumin in these complexes was improved but still short-term, and photostability of curcumin was impaired as compared to curcumin dissolved in methanol (2,4). Due to the low concentration and limited stability of curcumin and the high excess of cyclodextrins required, these preparations are not suitable for therapeutic use. These complexes were formed by contacting curcumin with cyclodextrin under neutral or slightly acidic conditions.
DE Patent Application No. 10233598 describes cosmetic or dermatological compositions containing curcumin and cyclodextrins. However, it is not demonstrated that the described compositions would contain curcumin in water-soluble form and the examples of the application describe only oil in water emulsions, which are not suitable for parenteral administration.
U.S. Pat. No. 5,702,881 to Brasile describes the addition of cyclodextrin to a preservation solution of organs intended for transplantation. The addition of curcumin dissolved in dimethyl sulfoxide to a preservation solution of organ transplants has also been described in the prior art (5). U.S. Patent Application No. 20090123904 further describes the addition of a positively charged cyclodextrin to organ preservation solution, preferentially combined with antioxidants resveratrol or curcumine. However, these compositions do not enable the delivery of curcumin into organ transplants at such concentrations, which would effectively protect ischemically damaged organ transplants against reperfusion injury.
The present invention seeks to alleviate the problems associated with curcumin administration by seeking novel methods to solubilize curcumin in concentrations high enough to allow administration in effective doses to human and animal subjects. Further, the present invention seeks to provide stable water-soluble formulations and compositions of curcumin which make possible the delivery of effective concentrations of curcumin into organs and tissues. The present invention also seeks to provide for the manufacture of pharmaceutical and nutraceutical formulations of curcumin. Finally, the present invention also seeks to provide compositions and methods for the protection of organs and cells.